Tirabrutinib Chemical Properties

Boiling point:

672.0±65.0 °C(Predicted)

Density 

1.412±0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO:65.0(Max Conc. mg/mL);143.02(Max Conc. mM)
DMSO:PBS (pH 7.2) (1:2):0.3(Max Conc. mg/mL);0.66(Max Conc. mM)
DMF:30.0(Max Conc. mg/mL);66.01(Max Conc. mM)
Ethanol:1.0(Max Conc. mg/mL);2.2(Max Conc. mM)

form 

A crystalline solid

pka

3.16±0.20(Predicted)

color 

White to yellow

InChIKey

SEJLPXCPMNSRAM-GOSISDBHSA-N

SMILES

N1(C2=CC=C(OC3=CC=CC=C3)C=C2)C2C(=NC=NC=2N)N([C@@H]2CCN(C(=O)C#CC)C2)C1=O

Tirabrutinib Usage And Synthesis

Description

Btk Kinase inhibitor is highly potent and selective orally administered, small molecule, and also named tirabrutinib, Brutons tyrosine kinase (BTK) inhibitor being developed by Ono pharmaceutical and its licensee Gilead Sciences for the treatment of autoimmune disorders and haematological malignancies. 

Uses

Tirabrutinib is a BTK inhibitor that was approved in Japan in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma.

brand name

Velexbru^TM

Biological Functions

In March 2020, tirabrutinib was approved in  Japan to treat primary central nervous system lymphoma (PCNSL).  Tirabrutinib shows excellent selectivity against all kinases with cysteines in the ATP-binding site corresponding to Cys481 in BTK with the exception of BMX, TXK, and TEC? However, it displays weaker  BTK inhibition than ibrutinib (IC50 = 6.8 nM vs. 0.47  nM).

General Description

Class: non-receptor tyrosine kinase
Treatment: PCNSL
Elimination half-life = 6.5–8 h
Protein binding = 91%

Mechanism of action

The selective inhibition of cell growth by Btk Kinase inhibitor was due to blocking of BTK-mediated signaling through AKT and cellular protein kinase D. It can inhibit autophosphorylation of the BTK at the Tyr223 position through the ERK, AKT and PKD signaling pathways.

Side effects

Adverse effects of the Btk Kinase inhibitor that occurred in some patients were rash, vomiting, neutropenia, arthralgia, and malaise, and drug-related Grade 3–4 Adverse effects were neutropenia, leukopenia, anemia, hypophosphatemia, PT-INR increased, pneumonitis, and acute myeloid leukemia. in prior Japanese studies, rash, hematologic adverse effects, erythema multiforme, and constipation were frequent adverse effects in a Phase I/II study of some patients with PCNSL, and rash, hematologic adverse effects, and stomatitis were the most common adverse effects in a Phase II study of some patients with WM.

Synthesis

The synthesis started from 4-phenoxyaniline (384), which was reacted with diethyl chloromalonate (385) in water in the presence of a phase transfer catalyst (TBAB) to give diethyl aminomalonate (386). Condensation with ethyl foraminate gave the pyrimidine derivative 387 in 87% yield. Subsequently, the pyridine diol 387 was converted to the corresponding dichloroaryl system 388 by treatment with phosphorus oxychloride in DMF, with simultaneous N-formylation of the aniline nitrogen, probably via a Vilsmeier-Haack mechanism. Substitution reactions with compound 389 required precise control of the stoichiometry to achieve adequate conversion. Treatment with sodium hydroxide to remove the formyl group gave the diamine intermediate 390. Subsequently, the azabenzimidazolone structure was established by a CDI-mediated reaction, followed by a second SNAr reaction with benzylamine (392) to afford diamine 393 as the dihydrochloride salt after acidic deprotection. Finally, pyrroline 393 was reacted with butyric acid (394) via a T3P-mediated amidation reaction, which subsequently gave tilarabrutinib hydrochloride.

target

BTK

Tirabrutinib(1351636-18-4)Related Product Information

• ONO-4059 (hydrochloride)
• Flumatinib
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